Next Article in Journal
Causes of Vaccine Hesitancy in Adults for the Influenza and COVID-19 Vaccines: A Systematic Literature Review
Next Article in Special Issue
Unbiased Identification of Dengue Virus Non-Structural Protein 1 Peptides for Use in Vaccine Design
Previous Article in Journal
Development of Modified Vaccinia Virus Ankara-Based Vaccines: Advantages and Applications
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Vaccines
Volume 10
Issue 9
10.3390/vaccines10091517
vaccines-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Understanding the Tissue Specificity of ZIKV Infection in Various Animal Models for Vaccine Development

by
Suyeon Kim
and
Ha Youn Shin
*
Department of Biomedical Science and Engineering, Konkuk University, Seoul 05029, Korea
*
Author to whom correspondence should be addressed.
Vaccines 2022, 10(9), 1517; https://doi.org/10.3390/vaccines10091517
Submission received: 22 July 2022 / Revised: 8 September 2022 / Accepted: 10 September 2022 / Published: 13 September 2022
(This article belongs to the Special Issue Latest Researches on Flavivirus Vaccines)
Browse Figures
Versions Notes

Abstract

:
Zika virus (ZIKV) is an arthropod-borne virus that belongs to the Flavivirus genus and is principally transmitted by Aedes aegypti mosquitoes. ZIKV infection often causes no or only mild symptoms, but it can also trigger severe consequences, including microcephaly in infants and Guillain-Barré syndrome, uveitis, and neurologic manifestations in adults. There is no ZIKV vaccine or treatment currently approved for clinical use. The primary target of ZIKV infection has been recognized as the maternal placenta, with vertical transmission to the fetal brain. However, ZIKV can also spread to multiple tissues in adults, including the sexual organs, eyes, lymph nodes, and brain. Since numerous studies have indicated that there are slightly different tissue-specific pathologies in each animal model of ZIKV, the distinct ZIKV tropism of a given animal model must be understood to enable effective vaccine development. Here, we comprehensively discussed the tissue specificity of ZIKV reported in each animal model depending on the genetic background and route of administration. This review should facilitate the selection of appropriate animal models when studying the fundamental pathogenesis of ZIKV infection, thereby supporting the design of optimal preclinical and clinical studies for the development of vaccines and therapeutics.

1. Introduction

1.1. Epidemiology and Clinical Manifestation of ZIKV Outbreaks

Zika virus (ZIKV) is a mosquito-transmitted RNA virus; it belongs to genus Flavivirus in the Flaviviridae family and is closely related to the dengue, yellow fever, Japanese encephalitis, and West Nile viruses [1]. Like other flaviviruses, ZIKV is enveloped and icosahedral and has an 11-kb positive single-stranded RNA genome. ZIKV was first isolated in 1947 from a rhesus monkey from the Zika forest of Uganda [2]. Sporadic ZIKV epidemic outbreaks were reported in French Polynesia (2013–2014), Brazil (2015), and South and Central America (2016) [3]. After human-to-human transmission was reported in 2016, the World Health Organization (WHO) declared ZIKV to be a major threat to public health. So far, two major strains of ZIKV have been identified: the African and Asian strains. Both are transmitted primarily via mosquitoes and can also be transmitted through mother-to-fetus transmission, breastfeeding, sexual contact, or blood transfusion [4]. The primary target tissues of ZIKV infection have been recognized as the maternal placenta and fetal brain. However, ZIKV can also be transmitted to other adult tissues, including the reproductive system, brain, eyes, and lymph nodes (Figure 1). ZIKV infection causes several clinical complications, including congenital microcephaly, autoimmune Guillain-Barré syndrome, and ocular diseases, such as uveitis and unilateral acute maculopathy [5,6,7,8].

1.2. Current Status of ZIKV Vaccine Development

Currently, there is no licensed ZIKV vaccine on the market. Since the primary target for ZIKV vaccination is pregnant women, a developed vaccine must be safe and effective for both pregnant women and their fetuses. As of July 2022, several ZIKV vaccines are undergoing phase 1 and 2 clinical trials [9,10,11,12] (Table 1). The major types of candidate vaccines include DNA, mRNA, inactivated virion, and peptide vaccines. The most commonly used immunogen is prM/E, which is the envelope protein of ZIKV. In early 2017, the first phase 2 clinical trial was approved for the ZIKV vaccine candidate VRC5283, which was a DNA-based vaccine developed by the National Institute of Allergy and Infectious disease (NIAID). VRC5283 consists of a DNA plasmid encoding the E and PrM proteins of the Asian strain of ZIKV [9,10]. Preclinical studies demonstrated that it could elicit neutralizing antibodies against ZIKV in both murine and non-human primate models.
Although various ZIKV vaccine candidates have been developed in the past few years, many challenges have limited their progression to clinical trials. The primary recipients of ZIKV vaccination would be pregnant women, but it has proven difficult to recruit participants for clinical trials. Safety and ethical issues mean that it can take a long time to recruit sufficient healthy study volunteers in ZIKV epidemic regions. Researchers have also found it difficult to conduct preclinical studies, given that ZIKV susceptibility and pathological features exhibit slight differences between humans and animal models of various genetic backgrounds. It is very important that we understand the pathological features of each animal model for ZIKV infection, as this will enable optimal animal models to be selected for preclinical studies and support successful progression to clinical studies.

1.3. Animal Models for Studying ZIKV

Several animal models have been used to explore the infection, transmission, etiology, and immune mechanisms of ZIKV. The most commonly used animal models for ZIKV studies are mice and nonhuman primates.

1.3.1. Mouse Models

Mice are the most widely used laboratory animals due to their low cost of breeding, short generation time, numerous litters, and small size. However, wild-type or immunocompetent mice, such as C57BL/6, ICR (CD-1), and SJL mice, are naturally resistant to ZIKV infection [3]. In humans, ZIKV infection stimulates the interferon (IFN)-α/β receptors and activates the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway to induce IFN-stimulated genes (ISGs) that are essential for innate immunity [13]. However, the NS5 protein of ZIKV binds and degrades STAT2 to disrupt IFN signaling [14]. In contrast, ZIKV NS5 does not bind efficiently to murine STAT2; this prevents the virus from escaping the innate immune system and allows mice to resist ZIKV infection.
To address this issue, researchers have often administered anti-IFN-α/β receptor antibodies to block IFN signaling in immunocompetent mice to improve ZIKV susceptibility [15]. Gordon and colleagues also recently created human STAT2 knock-in (KI) mice by introducing human STAT2 into the mouse Stat2 locus [16]. Alternatively, many research groups have used immunocompromised mice with genetic deficiencies in the IFN pathway, including IFN-α/β receptor knockout (KO) (A129), IFN-α/β/γ receptor KO (AG129), Stat2 KO, Irf3/Irf5 double KO, and Irf3/Irf5/Ifr7 triple KO mice [17,18,19,20,21,22,23,24]. These immunodeficient mice are susceptible to ZIKV infection and display various viral pathologies found in humans [17,19,25,26]. Indeed, these mouse models have been used for the preclinical evaluation of vaccine candidates. Ifnar1−/− mice were employed to test the protective efficacy of a DNA vaccine candidate encoding ZIKV prM/E (GLS-5700) against testicular damage caused by ZIKV infection [27]. Both A129 mice and anti-Ifnar1 antibody-treated immunocompetent mice were used to evaluate the protective efficacy of a prM/E mRNA vaccine and a live-attenuated vaccine candidate against placental and fetal damage [28,29]. CD-1 and AG129 mice were used to evaluate the preclinical immunogenicity and efficacy of a purified inactivated ZIKV vaccine candidate (PIZV) [30]. Nevertheless, the fetal developmental process and placental structure in mice differ from those in humans [31,32,33,34]. Moreover, these mouse models cannot represent the developmental processes of the human brain and central nervous system [34,35] and therefore do not display ZIKV-related Guillain-Barré syndrome. These distinct features might limit the usefulness of mouse models in this context.

1.3.2. Nonhuman Primate Models

Nonhuman primates are very similar to humans in terms of their immune system, reproduction, and developmental processes. Several reports have shown that nonhuman primates of different species, including rhesus, cynomolgus, and pigtailed macaques, can be infected with various ZIKV strains either subcutaneously or intravenously (Table 2). A preclinical study was also conducted in rhesus macaques to demonstrate the efficacy of the DNA vaccine candidate VRC5283 [36]. The persistent efficacy of a ZPIV vaccine candidate was evaluated in rhesus monkeys [37]. Although nonhuman primates offer many advantages arising from their close resemblance to humans, their use in preclinical studies is limited by ethical issues, high breeding costs, and limitations in group size. Nevertheless, it is evident that the use of nonhuman primate models can enable accurate research for ZIKV [17].
Clearly, each animal model has advantages and limitations for studying ZIKV. In this review, we comprehensively discuss the multiple tissue tropism of ZIKV and the tissue-specific symptoms revealed in each animal model. This review will provide insight into the selection of animal models and tissue types suitable for preclinical studies seeking to develop vaccines and treatments for ZIKV outbreaks.

2. ZIKV Transmission from Maternal Placenta to Fetal Brain

A key feature of congenital ZIKV syndrome is microcephaly, wherein an infant displays a smaller-than-normal head due to immature brain development during pregnancy. Severe microcephaly is correlated with mental retardation, learning disability, and poor motor function [38]. ZIKV infection in pregnant women has received considerable attention due to the vertical transmission of ZIKV from the maternal placenta to fetuses, resulting in high rates of microcephaly [39,40]. Several studies have demonstrated that ZIKV can replicate in placental cells [41,42,43] and in fetal endothelial cells upon the infection of the placental barrier [44]. Accordingly, many researchers have focused primarily on understanding the mechanisms of ZIKV infection in the placenta and fetus when seeking to develop vaccines and therapeutics.

2.1. Mice

Mouse models have shown slight differences in viral susceptibility to and clinical manifestations of ZIKV infection in the maternal placenta and fetus depending on the genetic background and/or route of administration. For example, the subcutaneous injection of ZIKV in immunocompetent mice, such as C57BL/6, CD-1, or SJL mice, yielded insignificant clinical signs and no viral replication due to the intact innate immunity [21,26,45]. However, several studies found that intravenous or intrauterine ZIKV infection in these mice induced viral replication in the placenta and the resorption of fetuses [26] (Table 2). When C57BL/6 mice were inoculated with a high dose of ZIKV via an intravenous route at embryonic day 9.5 (E9.5), fetuses were resorbed at day E17.5 even though the ZIKV RNA was only sparsely detected in the fetal head [46]. When ZIKV was inoculated directly into the uterus of pregnant CD-1 mice, viral RNA was observed in the uterine horn, placenta, and fetal head [47]. This inoculation also increased fetal abortion, placental inflammation, and IFN-β levels. In ICR mice, the injection of ZIKV into the embryonic brains at E15.5 led to fetal death and microcephaly [24,48]. The intravenous injection of ZIKV into SJL mice also induced the congenital malformation of the brain [49]. Human STAT2 KI mice and immunodeficient mice showed more enhanced viral susceptibility and evident clinical symptoms. Even the subcutaneous injection of ZIKV into human STAT2 KI mice resulted in higher levels of ZIKV RNA in the placenta and fetal heads compared with the immunocompetent wild-type mice [16]. The subcutaneous injection of ZIKV into IFN-deficient A129 and AG129 mice resulted in a small fetal head and the detection of viral RNA in the placenta and fetal head [50,51]. Taken together, these results indicate that mice are naturally resistant to ZIKV infection but that mouse models may exhibit human-like symptoms such as microcephaly depending on their genetic background and/or the route of ZIKV administration.

2.2. Non-Human Primates

Compared with the mouse models, the pathological symptoms of ZIKV infection during pregnancy in nonhuman primates are more analogous to those of humans [52]. Several studies have shown that the subcutaneous injection of ZIKV in rhesus monkeys induced robust placental and fetal inflammation, placental dysfunction, and fetal neuropathology, such as neural progenitor cell dysfunction and neuronal apoptosis [53,54]. The direct inoculation of ZIKV into the amniotic fluid at early pregnancy resulted in more severe symptoms, including loss of neural precursor cells and early fetal death [55]. The subcutaneous inoculation of ZIKV into pregnant pigtail monkeys induced fetal brain damage, such as fetal brain growth arrest and a significant loss of fetal neural progenitor cells [56,57]. The intramuscular injection of ZIKV into a rat-sized marmoset induced human-like fetal neurodevelopmental abnormalities and spontaneous fetal loss accompanied by extensive viral replication in the placenta [58]. Although the gestational duration is shorter in these nonhuman primates than in humans, the above-described results indicate that nonhuman primates may recapitulate the human situation for clinical symptoms of ZIKV infection during pregnancy.
Table
Table 2. Pathological features of ZIKV infection in maternal placentas and fetuses of animal models.
Table 2. Pathological features of ZIKV infection in maternal placentas and fetuses of animal models.
Animal Species ZIKV StrainRoute of
Administration		Pathologic FeaturesReference
Mouse
C57BL/6PRVABC59IntravenousFetal resorption, little or no viral RNA in placenta and fetal heads[46]
CD-1IBH 30656,
PRVABC59, FS13025		IntrauterinePlacental dysfunction and inflammation, increased aborted fetus numbers, reduced neonatal brain and cortical thickness[47]
SJLZIKV-BRIntravenousMalformations of congenital brain, intrauterine growth restriction, upregulation of apoptosis-related genes[49]
ICRGZ01Intra-ventricularFetal death, microcephaly[48]
Human STAT2 KIZIKV-Dak-MASubcutaneousViral RNA in placenta and fetal heads[16]
Ifnar1−/−FSS13025SubcutaneousFetal resorption, reduced fetal weight and size[59]
A129PRVABC59SubcutaneousViral RNA in placenta, maternal brain, and fetal heads, reduced fetal weight[51]
AG129P6-740SubcutaneousViral RNA in placenta and fetal heads, decreased weight and head length[50]
Monkey
Rhesus macaquePRVABC59 SubcutaneousViral RNA in fetus, increased maternal-placental-fetal inflammatory response, placenta damage, reduced oxygen permeability of the placental villi[53]
Rhesus macaqueZIKV-BRSubcutaneousFetal neuropathology, neuroprogenitor apoptosis and gliosis, placental pathology[54]
Rhesus macaqueSPH 2015Intra-amnioticViral RNA in fetal and placental tissues, early death of fetus, fetal ZIKV neurotropism, neuropathology at the end of gestation[55]
Pigtail macaqueFSS13025SubcutaneousReduced growth of the fetal biparietal diameter and fetal brain lesions, viral RNA in fetal brain and placenta[56]
Pigtail macaqueFSS13025,
ZIKV-BR		SubcutaneousDecreased fetal non-cortical brain volume, injury in ependymal epithelium with underlying gliosis, reduced late fetal neuronal progenitor cells in the subventricular zone[57]
MarmosetSPH 2015IntramuscularFetal demise and abortion, increase of proinflammatory cytokines, fetal neurocellular disorganization, viral RNA in placenta and fetus[58]

3. ZIKV Infection in Reproductive Organs

3.1. Female Animal Models

In addition to vertical transmission from mother to fetus, ZIKV can be transmitted through sexual contact and can cause genital infection. Several research groups have demonstrated that ZIKV can infect the female reproductive organs and detected ZIKV RNA in the female genital tract in animal models, including cervical mucus, vaginal secretions, and ovaries [60,61] (Table 3). Even in immunocompetent C57BL/6 mice, vaginal infection with ZIKV resulted in local viral replication [60]. In immunodeficient Ifnar1−/− and Irf3−/−Irf7−/− mice, vaginal ZIKV infection induced higher levels of viral replication. In C57BL/6 mice treated with anti-Ifnar1 monoclonal Ab (mAb) to block the IFN pathway, viral RNA was detected in the vaginal lumen, cervix, ovaries, and uterine horns after intravaginal inoculation of ZIKV [62]. Subcutaneous inoculation of ZIKV in anti-Ifnar1 mAb-treated T-cell-deficient CD8−/− and TCRβδ−/− mice resulted in higher ovarian cell death compared to that in C57BL/6 mice [61]. Transmission of ZIKV from female reproductive organs has also been found in nonhuman primates. In rhesus monkeys, direct injection of ZIKV into the vagina led to preferential viral replication in the female reproductive tract [63]. Even after subcutaneous injection, ZIKV RNA was detected in the vaginal secretions and reproductive tissues of female rhesus and cynomolgus monkeys [64].

3.2. Male Animal Models

ZIKV can also infect the male reproductive system. Cohort studies have revealed that the ZIKV RNA can be detected in semen and can persist in the male reproductive tract [65,66,67,68,69]. Persistent ZIKV replication in the male genital tract can cause genitourinary symptoms such as inflammation of the prostate gland, bloody semen, and infertility. The subcutaneous inoculation of ZIKV into C57BL/6 and Ifnar1−/− mice resulted in decreased testis size and testosterone levels and degradation of the seminiferous tubule due to persistent viral replication in semen [15,70] (Table 3). On the other hand, infection of ZIKV via an intraperitoneal route into immunodeficient Ifnar1−/− and AG129 mice caused inflammation in the testis and epididymis, leading to male infertility [23,71,72]. Similarly, ZIKV RNA was detected in monkey testicles after subcutaneous injection [73].
Table
Table 3. Effects of ZIKV on reproductive systems in animal models.
Table 3. Effects of ZIKV on reproductive systems in animal models.
Animal SpeciesZIKV StrainRoute of
Administration		Pathologic FeaturesReference
Female
C57BL/6FSS13025IntravaginalViral RNA in vagina until 4 dpi (local replication)[60]
Ifnar1−/−, Irf3−/−Irf7−/−FSS13025IntravaginalHigh viral RNA levels in vagina[60]
C57BL/6J
(+ anti-Ifnar1 mAb)		ZIKV-BRIntravaginalZIKV in the vaginal lumen, cervix, ovaries, uterine horns[62]
C57BL/6,
CD8−/−, TCRβδ−/−
(+ anti-Ifnar1 mAb)		Dakar 41525,
PRVABC59, H/PF/2013		SubcutaneousViral replicates in ovary, increased inflammation in the ovary, acute oophoritis[61]
Rhesus macaqueSPH 2015IntravaginalViral RNA in female reproductive tract, increased cytokine levels in cervicovaginal lavage[63]
Rhesus macaque,
Cynomolgus macaque		Thai,
Puerto Rican		SubcutaneousViral RNA in female reproductive tissues[64]
Male
C57BL/6
(+ anti-Ifnar1 mAb)		Dakar 41519,
H/PF/2013		SubcutaneousViral RNA in the testis and epididymis, decreased testis size, low testosterone level, infected spermatogonia, degradation of seminiferous tubule[15]
Ifnar−/−MEX2-81SubcutaneousViral RNA and antigen in the epididymal lumen, testicular atrophy, low testosterone level[70]
Ifnar−/−SMGC-1 IntraperitonealAtrophy of the reproductive tract, virus in testicles, increased inflammation in the testis and epididymis[71]
AG129PRVABC59IntraperitonealViral RNA and virus in semen, increased inflammation in testis and epididymis[72]
AG129SL1602IntraperitonealViral RNA in testis and epididymis, increased inflammation in testis[23]
Cynomolgus macaqueIBH30656,
PRVABC59, FSS13025		SubcutaneousVirus in the testis[73]

4. ZIKV Tropism in Other Tissues

4.1. Brain

One unique feature of ZIKV infection is that it preferentially infects the fetal brain, causing congenital or postnatal microcephaly [74]. ZIKV can also affect the adult brain to cause Guillain-Barré syndrome, an autoimmune disease in which the immune system attacks the peripheral nervous system [4,75]. Guillain-Barré syndrome further leads to muscle weakness, paralysis, and ultimately death [76,77,78]. Several animal models can recapitulate the brain or neurological damage seen in humans (Table 4). In C57BL/6 mice treated with anti-Ifnar1 mAb, either the subcutaneous or the intraperitoneal injection of ZIKV induced inflammatory responses and neuronal cell death in the brain and spinal cord [79]. The subcutaneous injection of ZIKV into human STAT2 KI mice resulted in high levels of viral RNA in the brain [16]. However, intraperitoneal infection yielded higher viral susceptibility (100% mortality) than that achieved with subcutaneous infection (40% mortality). In immunodeficient A129 mice, ZIKV RNA was also detected in adult brain tissue after subcutaneous injection, and nuclear fragments were found with necrosis in a portion of the hippocampus [80]. Adult AG129 mice showed high viral susceptibility with severe brain pathology after subcutaneous, intraperitoneal, or foot-pad ZIKV inoculation [18,19,81]. Histopathological examination revealed neutrophil infiltration in the hippocampus, neuronal degeneration, and necrotic cell debris. High viral RNA loads were also observed in the brain and spinal cords. Mice with triple knockout of Irf3, Ifr5, and Irf7 were highly vulnerable to subcutaneous, intraperitoneal, or intravenous ZIKV infection and developed neurological diseases such as hindlimb weakness and paralysis [45]. Taken together, these animal studies clearly demonstrated that ZIKV can damage the adult brain and nervous tissue, although the detailed mechanism underlying Guillain-Barré syndrome remains to be fully elucidated.

4.2. Eyes

Several case reports have shown that ZIKV infection can cause ocular diseases, such as conjunctivitis and optic nerve abnormalities [82,83]. These ocular pathologies have also been observed in animal models (Table 4). The subcutaneous injection of ZIKV into C57BL/6 mice preferentially infected the cornea and retina, resulting in inflammation of the optic nerves and the distortion of eye structures [84]. The direct inoculation of ZIKV into the eyes of C57BL/6 and ISG15 knockout mice yielded ocular abnormalities, including pigment clumping and retinal pigment epithelium (RPE) atrophy [85]. ISG15 knockout mice showed more severe retinitis and retinal cell death with higher levels of ZIKV RNA in the retina. ZIKV inoculation to the anterior chamber of the eye or by intraperitoneal route in C57BL/6 and Ifnar1 knockout mice induced innate immune responses and increased intraocular pressure (IOP), which is a hallmark of glaucoma (a major cause of blindness) [86]. Posterior retinal cell death was observed even following ZIKV infection in the anterior part of the eye, suggesting that ZIKV may spread from the anterior to posterior part of the eye [87]. Together, these results indicate that ZIKV can affect the optic nerve, which is part of the central nervous system.

4.3. Lymph Nodes

ZIKV infection in lymph nodes was commonly found in nonhuman primates (Table 4). Following the subcutaneous injection of ZIKV into rhesus monkeys, ZIKV could persist up to 72 days in the lymph nodes even after the virus had been cleared from the peripheral blood [88]. Among the various cell types within lymphoid tissues, ZIKV RNA was mainly found in the macrophage and B cell subsets, whereas little or no ZIKV RNA was found in the subsets of dendritic cells and T cells [89]. Intravenous inoculation of ZIKV into rhesus monkeys clearly induced hyperplasia of the lymph nodes, but the activation of lymphocytic cells was limited to the monocyte and B cell subsets [90]. Subcutaneous ZIKV injection in pigtail monkeys also resulted in an innate immune response, with increased proinflammatory cytokine levels and long-term ZIKV persistence in the lymph nodes [91]. Vaginal inoculation of ZIKV-infected semen into baboons yielded the persistence of ZIKV RNA in lymph nodes [92]. This persistent ZIKV infection in lymph nodes and lymphocytic inflammatory responses found in nonhuman primates recapitulate the pathogenic features of ZIKV infection in humans.
Table
Table 4. Pathologic features of ZIKV dissemination in brain, eyes, and lymph nodes of animal models.
Table 4. Pathologic features of ZIKV dissemination in brain, eyes, and lymph nodes of animal models.
Animal SpeciesZIKV StrainRoute of
Administration		Pathologic FeaturesReference
Brain
C57BL/6
(+ anti-Ifnar1 Ab)		Dakar 41525 Subcutaneous,
intraperitoneal		Lesions in CNS, high viremia, decreased weight[79]
Human STAT2 KIZIKV-Dak-MASubcutaneousViral RNA in brain[16]
A129MP1751 SubcutaneousLesions in brain, viral RNA in the brain[80]
AG129H/PF/2013 Footpad,
intraperitoneal		Virus in brain, neurodegeneration, myofiber necrosis, inflammatory cell infiltration, pathology in brain[18]
AG129P6–740 SubcutaneousViral load in the brain, limb weakness, paralysis, increased neurological signs including locomotor hyperactivity, tremor, and seizure[19]
AG129MR 766IntraperitonealParalysis, neurodegeneration, acute encephalitis, viral antigen in brain and spinal cord[81]
Ifnar−/−,
Irf3−/−Irf5−/−Ifr7−/− TKO		H/PF/2013,
MR766		Subcutaneous,
intravenous,
intraperitoneal		Viral RNA in brain and spinal cord, increased neurological disease signs including hindlimb weakness and paralysis[45]
Eye
C57BL/6PRVABC59SubcutaneousChorioretinal lesions, induced local inflammation and cellular infiltration[84]
C57BL/6,
ISG15−/−		PRVABC59IntravitrealChorioretinal atrophy with RPE mottling, increased multiple inflammatory and antiviral response genes in the retina, severe chorioretinitis coinciding with retinal cell death and higher virus replication in ISG15−/− mice[85]
C57BL/6,
Ifnar1−/−		PRVABC59Anterior segment of eyes,
intraperitoneal		Increased intraocular pressure, chorioretinal atrophy, increased expression of inflammatory mediators, retinal ganglion cell death[86]
Lymph node
Rhesus macaquePRVABC59,
Brazil/ZKV/2015		SubcutaneousVirus in lymph nodes in both paracortical regions, germinal centers, and cerebrospinal fluid, upregulation of proinflammatory and anti-apoptotic signaling pathways[88]
Rhesus monkeysZIKV-BRIntravenousActivation of lymphoid tissues[90]
Rhesus monkeysPRVABC59SubcutaneousVirus in multiple lymphoid tissues, viral RNA in lymphoid and joint/muscle tissues[89]
Pigtail macaqueBrazil_2015_MGSubcutaneousIncrease of innate immune cells in blood, lymph nodes, and mucosal tissues, activation of monocytes in peripheral lymph nodes[91]
Olive baboonH/PF/2013,
PRVABC59		Vaginal deposition of ZIKV-infected semenViral RNA in lymph nodes[92]

5. Discussion

The selection of appropriate animal models for preclinical studies is essential for the successful development of antiviral vaccines or therapeutics. Particularly, mice and nonhuman primates have been commonly used in animal studies of ZIKV infection. However, each animal model displays slightly different clinical symptoms under ZIKV infection depending on the genetic background and/or the route of viral inoculation. Since immunocompetent wild-type mice are resistant to ZIKV infection under natural conditions, alternative methods such as high-dose injection of ZIKV or treatment with antibodies targeting IFN receptors have been used [79]. Alternatively, immunocompromised mice that are genetically modified to disrupt IFN signaling pathways have been used to study ZIKV infection [50,51]. Several studies have demonstrated that IFN-deficient immunocompromised mice are more susceptible to ZIKV infection and show more severe pathological symptoms than immunocompetent mice. Nonhuman primates have also been used; despite the high cost, group size limitations, and ethical concerns, they have gestational and fetal development processes more analogous to those of humans [31]. In nonhuman primates, subcutaneous or intravenous ZIKV administration induced a relatively similar pattern of lesions, while mice exhibited more severe pathologic symptoms following intravenous or intraperitoneal injection than with subcutaneous injection.
Although different types of animal models show slightly different levels of clinical manifestation, a common finding is that ZIKV can infect multiple tissue types and induce tissue-specific symptoms (Figure 2). Indeed, ZIKV exhibits broad tissue tropism, including to maternal placenta, fetal brain, reproductive systems, adult brain, eyes, and lymph nodes, under diverse routes of infection. Vertical transmission of ZIKV from maternal placenta to fetal brain causes microcephaly or fetal death. Sexual transmission of ZIKV results in the infection of both male and female reproductive systems. Several studies have shown that ZIKV can persist in male semen, whereas female genital infection is more transient [68]. The central nervous system is also susceptible to ZIKV infection. Notably, ZIKV can replicate in the adult brain and spinal cord, causing neurological disorders such as paralysis or Guillain-Barré syndrome [8]. As part of the central nervous system, the optic nerve can disseminate ZIKV into the eye, leading to conjunctivitis or even glaucoma [86]. ZIKV can also spread to lymph nodes, causing lymphocyte accumulation, inflammation, and the activation of macrophage and B-cell subsets [89].
Since animal studies have shown that the extent of ZIKV pathology is dependent on the tissue tropism and route of administration, it is essential that we understand the tissue-specific symptoms and most relevant routes of ZIKV inoculation. Only then will researchers be able to accurately assess the efficacy and safety of vaccine candidates. If an animal model showing ZIKV infection only in the mother’s placenta or fetus is selected for a preclinical study, the effect of the vaccine candidate on other tissues will be veiled. This can lead to misunderstandings of the efficacy and safety of vaccine candidates and lead to the failure of clinical studies. Accordingly, it would be more appropriate to use immunodeficient mice, such as A129 or AG129 mice, for preclinical studies. Systemic inoculation of ZIKV, such as via intraperitoneal or intravenous routes, can induce broad disease manifestations, and subcutaneous inoculation can also cause systemic disease [18,19,23,50,51,72,80,81,93,94,95]. When immunocompetent mice are used for preclinical studies, the direct injection of ZIKV into the target organ, such as vaginal or intracerebral inoculation, may induce more pronounced symptoms for evaluating the vaccine efficacy [19,60,96]. Human STAT2 KI mice can be used as an alternative to immunocompetent wild-type mice [16]. Even subcutaneous inoculation of ZIKV into pregnant STAT2 KI mice resulted in higher levels of ZIKV RNA in the placenta and fetal head compared with wild-type mice. Although human STAT2 knock-in mice can recapitulate the hallmarks of human infection, this model needs further improvement as it requires a mouse-adapted ZIKV strain and exhibits low permissiveness to infection in adult mice. In addition, non-human primate models will be more useful for testing vaccine efficacy against certain diseases, such as Guillain-Barré syndrome, that are difficult to study in mouse models due to structural differences. This review comprehensively discussed the clinical symptoms of different animal models depending on the route of ZIKV inoculation and tissue-specific lesions. It will provide insight into selecting a suitable animal model and may suggest strategies for preclinical studies on evaluating ZIKV vaccines and therapeutics.

Author Contributions

Conceptualization, S.K. and H.Y.S.; methodology, S.K. and H.Y.S.; investigation, S.K.; writing—original draft preparation, S.K.; writing—review and editing, H.Y.S.; visualization, S.K.; supervision, H.Y.S.; project administration, H.Y.S.; funding acquisition, H.Y.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Ministry of Health & Welfare (Korea), grant number HI18C2177.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Sharma, V.; Sharma, M.; Dhull, D.; Sharma, Y.; Kaushik, S.; Kaushik, S. Zika virus: An emerging challenge to public health worldwide. Can. J. Microbiol. 2020, 66, 87–98. [Google Scholar] [CrossRef] [PubMed]
  2. Dick, G.W.; Kitchen, S.F.; Haddow, A.J. Zika virus. I. Isolations and serological specificity. Trans. R. Soc. Trop. Med. Hyg. 1952, 46, 509–520. [Google Scholar] [CrossRef]
  3. Shaily, S.; Upadhya, A. Zika virus: Molecular responses and tissue tropism in the mammalian host. Rev. Med. Virol. 2019, 29, e2050. [Google Scholar] [CrossRef] [PubMed]
  4. Song, B.H.; Yun, S.I.; Woolley, M.; Lee, Y.M. Zika virus: History, epidemiology, transmission, and clinical presentation. J. Neuroimmunol. 2017, 308, 50–64. [Google Scholar] [CrossRef] [PubMed]
  5. Miner, J.J.; Diamond, M.S. Zika Virus Pathogenesis and Tissue Tropism. Cell Host Microbe 2017, 21, 134–142. [Google Scholar] [CrossRef]
  6. Kodati, S.; Palmore, T.N.; Spellman, F.A.; Cunningham, D.; Weistrop, B.; Sen, H.N. Bilateral posterior uveitis associated with Zika virus infection. Lancet 2017, 389, 125–126. [Google Scholar] [CrossRef]
  7. de Paula Freitas, B.; Ventura, C.V.; Maia, M.; Belfort, R., Jr. Zika virus and the eye. Curr. Opin. Ophthalmol. 2017, 28, 595–599. [Google Scholar] [CrossRef]
  8. Duca, L.M.; Beckham, J.D.; Tyler, K.L.; Pastula, D.M. Zika Virus Disease and Associated Neurologic Complications. Curr. Infect. Dis. Rep. 2017, 19, 4. [Google Scholar] [CrossRef]
  9. Diamond, M.S.; Ledgerwood, J.E.; Pierson, T.C. Zika Virus Vaccine Development: Progress in the Face of New Challenges. Annu. Rev. Med. 2019, 70, 121–135. [Google Scholar] [CrossRef]
  10. Lin, H.H.; Yip, B.S.; Huang, L.M.; Wu, S.C. Zika virus structural biology and progress in vaccine development. Biotechnol. Adv. 2018, 36, 47–53. [Google Scholar] [CrossRef]
  11. Maslow, J.N. Zika Vaccine Development-Current Progress and Challenges for the Future. Trop. Med. Infect. Dis. 2019, 4, 104. [Google Scholar] [CrossRef] [PubMed]
  12. Pielnaa, P.; Al-Saadawe, M.; Saro, A.; Dama, M.F.; Zhou, M.; Huang, Y.; Huang, J.; Xia, Z. Zika virus-spread, epidemiology, genome, transmission cycle, clinical manifestation, associated challenges, vaccine and antiviral drug development. Virology 2020, 543, 34–42. [Google Scholar] [CrossRef]
  13. Honda, K.; Takaoka, A.; Taniguchi, T. Type I interferon [corrected] gene induction by the interferon regulatory factor family of transcription factors. Immunity 2006, 25, 349–360. [Google Scholar] [CrossRef] [PubMed]
  14. Grant, A.; Ponia, S.S.; Tripathi, S.; Balasubramaniam, V.; Miorin, L.; Sourisseau, M.; Schwarz, M.C.; Sanchez-Seco, M.P.; Evans, M.J.; Best, S.M.; et al. Zika Virus Targets Human STAT2 to Inhibit Type I Interferon Signaling. Cell Host Microbe 2016, 19, 882–890. [Google Scholar] [CrossRef]
  15. Govero, J.; Esakky, P.; Scheaffer, S.M.; Fernandez, E.; Drury, A.; Platt, D.J.; Gorman, M.J.; Richner, J.M.; Caine, E.A.; Salazar, V.; et al. Zika virus infection damages the testes in mice. Nature 2016, 540, 438–442. [Google Scholar] [CrossRef]
  16. Gorman, M.J.; Caine, E.A.; Zaitsev, K.; Begley, M.C.; Weger-Lucarelli, J.; Uccellini, M.B.; Tripathi, S.; Morrison, J.; Yount, B.L.; Dinnon, K.H., 3rd; et al. An Immunocompetent Mouse Model of Zika Virus Infection. Cell Host Microbe 2018, 23, 672–685.e6. [Google Scholar] [CrossRef]
  17. Nazerai, L.; Scholler, A.S.; Rasmussen, P.O.S.; Buus, S.; Stryhn, A.; Christensen, J.P.; Thomsen, A.R. A New In Vivo Model to Study Protective Immunity to Zika Virus Infection in Mice With Intact Type I Interferon Signaling. Front. Immunol. 2018, 9, 593. [Google Scholar] [CrossRef]
  18. Aliota, M.T.; Caine, E.A.; Walker, E.C.; Larkin, K.E.; Camacho, E.; Osorio, J.E. Correction: Characterization of Lethal Zika Virus Infection in AG129 Mice. PLoS Negl. Trop. Dis. 2016, 10, e0004750. [Google Scholar] [CrossRef] [PubMed]
  19. Julander, J.G.; Siddharthan, V. Small-Animal Models of Zika Virus. J. Infect. Dis. 2017, 216, S919–S927. [Google Scholar] [CrossRef]
  20. Espinosa, D.; Mendy, J.; Manayani, D.; Vang, L.; Wang, C.; Richard, T.; Guenther, B.; Aruri, J.; Avanzini, J.; Garduno, F.; et al. Passive Transfer of Immune Sera Induced by a Zika Virus-Like Particle Vaccine Protects AG129 Mice Against Lethal Zika Virus Challenge. eBioMedicine 2018, 27, 61–70. [Google Scholar] [CrossRef] [Green Version]
  21. Rossi, S.L.; Tesh, R.B.; Azar, S.R.; Muruato, A.E.; Hanley, K.A.; Auguste, A.J.; Langsjoen, R.M.; Paessler, S.; Vasilakis, N.; Weaver, S.C. Characterization of a Novel Murine Model to Study Zika Virus. Am. J. Trop. Med. Hyg. 2016, 94, 1362–1369. [Google Scholar] [CrossRef] [PubMed]
  22. Salvo, M.A.; Kingstad-Bakke, B.; Salas-Quinchucua, C.; Camacho, E.; Osorio, J.E. Zika virus like particles elicit protective antibodies in mice. PLoS Negl. Trop. Dis. 2018, 12, e0006210. [Google Scholar] [CrossRef] [PubMed]
  23. Jacobs, S.; Delang, L.; Verbeken, E.; Neyts, J.; Kaptein, S.J.F. A Viral Polymerase Inhibitor Reduces Zika Virus Replication in the Reproductive Organs of Male Mice. Int. J. Mol. Sci. 2019, 20, 2122. [Google Scholar] [CrossRef] [PubMed]
  24. Zhu, X.; Li, C.; Afridi, S.K.; Zu, S.; Xu, J.W.; Quanquin, N.; Yang, H.; Cheng, G.; Xu, Z. E90 subunit vaccine protects mice from Zika virus infection and microcephaly. Acta Neuropathol. Commun. 2018, 6, 77. [Google Scholar] [CrossRef]
  25. Takaki, H.; Oshiumi, H.; Shingai, M.; Matsumoto, M.; Seya, T. Development of mouse models for analysis of human virus infections. Microbiol. Immunol. 2017, 61, 107–113. [Google Scholar] [CrossRef]
  26. Caine, E.A.; Jagger, B.W.; Diamond, M.S. Animal Models of Zika Virus Infection during Pregnancy. Viruses 2018, 10, 598. [Google Scholar] [CrossRef]
  27. Griffin, B.D.; Muthumani, K.; Warner, B.M.; Majer, A.; Hagan, M.; Audet, J.; Stein, D.R.; Ranadheera, C.; Racine, T.; De La Vega, M.A.; et al. DNA vaccination protects mice against Zika virus-induced damage to the testes. Nat. Commun. 2017, 8, 15743. [Google Scholar] [CrossRef]
  28. Richner, J.M.; Himansu, S.; Dowd, K.A.; Butler, S.L.; Salazar, V.; Fox, J.M.; Julander, J.G.; Tang, W.W.; Shresta, S.; Pierson, T.C.; et al. Modified mRNA Vaccines Protect against Zika Virus Infection. Cell 2017, 169, 176. [Google Scholar] [CrossRef]
  29. Richner, J.M.; Jagger, B.W.; Shan, C.; Fontes, C.R.; Dowd, K.A.; Cao, B.; Himansu, S.; Caine, E.A.; Nunes, B.T.D.; Medeiros, D.B.A.; et al. Vaccine Mediated Protection Against Zika Virus-Induced Congenital Disease. Cell 2017, 170, 273–283.e12. [Google Scholar] [CrossRef]
  30. Baldwin, W.R.; Livengood, J.A.; Giebler, H.A.; Stovall, J.L.; Boroughs, K.L.; Sonnberg, S.; Bohning, K.J.; Dietrich, E.A.; Ong, Y.T.; Danh, H.K.; et al. Purified Inactivated Zika Vaccine Candidates Afford Protection against Lethal Challenge in Mice. Sci. Rep. 2018, 8, 16509. [Google Scholar] [CrossRef]
  31. Newman, C.; Friedrich, T.C.; O’Connor, D.H. Macaque monkeys in Zika virus research: 1947-present. Curr. Opin. Virol. 2017, 25, 34–40. [Google Scholar] [CrossRef] [PubMed]
  32. Grigsby, P.L. Animal Models to Study Placental Development and Function throughout Normal and Dysfunctional Human Pregnancy. Semin. Reprod. Med. 2016, 34, 11–16. [Google Scholar] [CrossRef] [PubMed]
  33. Blankenship, T.N.; Enders, A.C.; King, B.F. Trophoblastic invasion and modification of uterine veins during placental development in macaques. Cell Tissue Res. 1993, 274, 135–144. [Google Scholar] [CrossRef] [PubMed]
  34. Carter, A.M. Animal models of human placentation--a review. Placenta 2007, 28 (Suppl. A), S41–S47. [Google Scholar] [CrossRef] [PubMed]
  35. Clancy, B.; Finlay, B.L.; Darlington, R.B.; Anand, K.J. Extrapolating brain development from experimental species to humans. Neurotoxicology 2007, 28, 931–937. [Google Scholar] [CrossRef]
  36. Van Rompay, K.K.A.; Keesler, R.I.; Ardeshir, A.; Watanabe, J.; Usachenko, J.; Singapuri, A.; Cruzen, C.; Bliss-Moreau, E.; Murphy, A.M.; Yee, J.L.; et al. DNA vaccination before conception protects Zika virus-exposed pregnant macaques against prolonged viremia and improves fetal outcomes. Sci. Transl. Med. 2019, 11, eaay2736. [Google Scholar] [CrossRef]
  37. Abbink, P.; Larocca, R.A.; Visitsunthorn, K.; Boyd, M.; De La Barrera, R.A.; Gromowski, G.D.; Kirilova, M.; Peterson, R.; Li, Z.; Nanayakkara, O.; et al. Durability and correlates of vaccine protection against Zika virus in rhesus monkeys. Sci. Transl. Med. 2017, 9, eaao4163. [Google Scholar] [CrossRef]
  38. Baud, D.; Gubler, D.J.; Schaub, B.; Lanteri, M.C.; Musso, D. An update on Zika virus infection. Lancet 2017, 390, 2099–2109. [Google Scholar] [CrossRef]
  39. Arora, N.; Sadovsky, Y.; Dermody, T.S.; Coyne, C.B. Microbial Vertical Transmission during Human Pregnancy. Cell Host Microbe 2017, 21, 561–567. [Google Scholar] [CrossRef]
  40. Pierson, T.C.; Diamond, M.S. The emergence of Zika virus and its new clinical syndromes. Nature 2018, 560, 573–581. [Google Scholar] [CrossRef]
  41. Quicke, K.M.; Bowen, J.R.; Johnson, E.L.; McDonald, C.E.; Ma, H.; O’Neal, J.T.; Rajakumar, A.; Wrammert, J.; Rimawi, B.H.; Pulendran, B.; et al. Zika Virus Infects Human Placental Macrophages. Cell Host Microbe 2016, 20, 83–90. [Google Scholar] [CrossRef] [PubMed]
  42. Miner, J.J.; Cao, B.; Govero, J.; Smith, A.M.; Fernandez, E.; Cabrera, O.H.; Garber, C.; Noll, M.; Klein, R.S.; Noguchi, K.K.; et al. Zika Virus Infection during Pregnancy in Mice Causes Placental Damage and Fetal Demise. Cell 2016, 165, 1081–1091. [Google Scholar] [CrossRef] [PubMed]
  43. Sheridan, M.A.; Yunusov, D.; Balaraman, V.; Alexenko, A.P.; Yabe, S.; Verjovski-Almeida, S.; Schust, D.J.; Franz, A.W.; Sadovsky, Y.; Ezashi, T.; et al. Vulnerability of primitive human placental trophoblast to Zika virus. Proc. Natl. Acad. Sci. USA 2017, 114, E1587–E1596. [Google Scholar] [CrossRef] [PubMed]
  44. Richard, A.S.; Shim, B.S.; Kwon, Y.C.; Zhang, R.; Otsuka, Y.; Schmitt, K.; Berri, F.; Diamond, M.S.; Choe, H. AXL-dependent infection of human fetal endothelial cells distinguishes Zika virus from other pathogenic flaviviruses. Proc. Natl. Acad. Sci. USA 2017, 114, 2024–2029. [Google Scholar] [CrossRef] [PubMed]
  45. Lazear, H.M.; Govero, J.; Smith, A.M.; Platt, D.J.; Fernandez, E.; Miner, J.J.; Diamond, M.S. A Mouse Model of Zika Virus Pathogenesis. Cell Host Microbe 2016, 19, 720–730. [Google Scholar] [CrossRef] [PubMed]
  46. Szaba, F.M.; Tighe, M.; Kummer, L.W.; Lanzer, K.G.; Ward, J.M.; Lanthier, P.; Kim, I.J.; Kuki, A.; Blackman, M.A.; Thomas, S.J.; et al. Zika virus infection in immunocompetent pregnant mice causes fetal damage and placental pathology in the absence of fetal infection. PLoS Pathog. 2018, 14, e1006994. [Google Scholar] [CrossRef] [PubMed]
  47. Vermillion, M.S.; Lei, J.; Shabi, Y.; Baxter, V.K.; Crilly, N.P.; McLane, M.; Griffin, D.E.; Pekosz, A.; Klein, S.L.; Burd, I. Intrauterine Zika virus infection of pregnant immunocompetent mice models transplacental transmission and adverse perinatal outcomes. Nat. Commun. 2017, 8, 14575. [Google Scholar] [CrossRef]
  48. Li, C.; Gao, F.; Yu, L.; Wang, R.; Jiang, Y.; Shi, X.; Yin, C.; Tang, X.; Zhang, F.; Xu, Z.; et al. A Single Injection of Human Neutralizing Antibody Protects against Zika Virus Infection and Microcephaly in Developing Mouse Embryos. Cell Rep. 2018, 23, 1424–1434. [Google Scholar] [CrossRef]
  49. Cugola, F.R.; Fernandes, I.R.; Russo, F.B.; Freitas, B.C.; Dias, J.L.; Guimaraes, K.P.; Benazzato, C.; Almeida, N.; Pignatari, G.C.; Romero, S.; et al. The Brazilian Zika virus strain causes birth defects in experimental models. Nature 2016, 534, 267–271. [Google Scholar] [CrossRef]
  50. Julander, J.G.; Siddharthan, V.; Park, A.H.; Preston, E.; Mathur, P.; Bertolio, M.; Wang, H.; Zukor, K.; Van Wettere, A.J.; Sinex, D.G.; et al. Consequences of in utero exposure to Zika virus in offspring of AG129 mice. Sci. Rep. 2018, 8, 9384. [Google Scholar] [CrossRef] [Green Version]
  51. Xie, X.; Kum, D.B.; Xia, H.; Luo, H.; Shan, C.; Zou, J.; Muruato, A.E.; Medeiros, D.B.A.; Nunes, B.T.D.; Dallmeier, K.; et al. A Single-Dose Live-Attenuated Zika Virus Vaccine with Controlled Infection Rounds that Protects against Vertical Transmission. Cell Host Microbe 2018, 24, 487–499.e5. [Google Scholar] [CrossRef] [PubMed]
  52. Nguyen, S.M.; Antony, K.M.; Dudley, D.M.; Kohn, S.; Simmons, H.A.; Wolfe, B.; Salamat, M.S.; Teixeira, L.B.C.; Wiepz, G.J.; Thoong, T.H.; et al. Highly efficient maternal-fetal Zika virus transmission in pregnant rhesus macaques. PLoS Pathog. 2017, 13, e1006378. [Google Scholar] [CrossRef] [PubMed]
  53. Hirsch, A.J.; Roberts, V.H.J.; Grigsby, P.L.; Haese, N.; Schabel, M.C.; Wang, X.; Lo, J.O.; Liu, Z.; Kroenke, C.D.; Smith, J.L.; et al. Zika virus infection in pregnant rhesus macaques causes placental dysfunction and immunopathology. Nat. Commun. 2018, 9, 263. [Google Scholar] [CrossRef] [PubMed]
  54. Martinot, A.J.; Abbink, P.; Afacan, O.; Prohl, A.K.; Bronson, R.; Hecht, J.L.; Borducchi, E.N.; Larocca, R.A.; Peterson, R.L.; Rinaldi, W.; et al. Fetal Neuropathology in Zika Virus-Infected Pregnant Female Rhesus Monkeys. Cell 2018, 173, 1111–1112.e10. [Google Scholar] [CrossRef]
  55. Coffey, L.L.; Keesler, R.I.; Pesavento, P.A.; Woolard, K.; Singapuri, A.; Watanabe, J.; Cruzen, C.; Christe, K.L.; Usachenko, J.; Yee, J.; et al. Intraamniotic Zika virus inoculation of pregnant rhesus macaques produces fetal neurologic disease. Nat. Commun. 2018, 9, 2414. [Google Scholar] [CrossRef]
  56. Adams Waldorf, K.M.; Stencel-Baerenwald, J.E.; Kapur, R.P.; Studholme, C.; Boldenow, E.; Vornhagen, J.; Baldessari, A.; Dighe, M.K.; Thiel, J.; Merillat, S.; et al. Fetal brain lesions after subcutaneous inoculation of Zika virus in a pregnant nonhuman primate. Nat. Med. 2016, 22, 1256–1259. [Google Scholar] [CrossRef]
  57. Adams Waldorf, K.M.; Nelson, B.R.; Stencel-Baerenwald, J.E.; Studholme, C.; Kapur, R.P.; Armistead, B.; Walker, C.L.; Merillat, S.; Vornhagen, J.; Tisoncik-Go, J.; et al. Congenital Zika virus infection as a silent pathology with loss of neurogenic output in the fetal brain. Nat. Med. 2018, 24, 368–374. [Google Scholar] [CrossRef]
  58. Seferovic, M.; Sanchez-San Martin, C.; Tardif, S.D.; Rutherford, J.; Castro, E.C.C.; Li, T.; Hodara, V.L.; Parodi, L.M.; Giavedoni, L.; Layne-Colon, D.; et al. Experimental Zika Virus Infection in the Pregnant Common Marmoset Induces Spontaneous Fetal Loss and Neurodevelopmental Abnormalities. Sci. Rep. 2018, 8, 6851. [Google Scholar] [CrossRef]
  59. Regla-Nava, J.A.; Elong Ngono, A.; Viramontes, K.M.; Huynh, A.T.; Wang, Y.T.; Nguyen, A.T.; Salgado, R.; Mamidi, A.; Kim, K.; Diamond, M.S.; et al. Cross-reactive Dengue virus-specific CD8(+) T cells protect against Zika virus during pregnancy. Nat. Commun. 2018, 9, 3042. [Google Scholar] [CrossRef]
  60. Yockey, L.J.; Varela, L.; Rakib, T.; Khoury-Hanold, W.; Fink, S.L.; Stutz, B.; Szigeti-Buck, K.; Van den Pol, A.; Lindenbach, B.D.; Horvath, T.L.; et al. Vaginal Exposure to Zika Virus during Pregnancy Leads to Fetal Brain Infection. Cell 2016, 166, 1247–1256.e4. [Google Scholar] [CrossRef] [Green Version]
  61. Caine, E.A.; Scheaffer, S.M.; Broughton, D.E.; Salazar, V.; Govero, J.; Poddar, S.; Osula, A.; Halabi, J.; Skaznik-Wikiel, M.E.; Diamond, M.S.; et al. Zika Virus Causes Acute Infection and Inflammation in the Ovary of Mice Without Apparent Defects in Fertility. J. Infect. Dis. 2019, 220, 1904–1914. [Google Scholar] [CrossRef] [PubMed]
  62. Scott, J.M.; Lebratti, T.J.; Richner, J.M.; Jiang, X.; Fernandez, E.; Zhao, H.; Fremont, D.H.; Diamond, M.S.; Shin, H. Cellular and Humoral Immunity Protect against Vaginal Zika Virus Infection in Mice. J. Virol. 2018, 92, e00038-18. [Google Scholar] [CrossRef] [PubMed]
  63. Carroll, T.; Lo, M.; Lanteri, M.; Dutra, J.; Zarbock, K.; Silveira, P.; Rourke, T.; Ma, Z.M.; Fritts, L.; O’Connor, S.; et al. Zika virus preferentially replicates in the female reproductive tract after vaginal inoculation of rhesus macaques. PLoS Pathog. 2017, 13, e1006537. [Google Scholar] [CrossRef]
  64. Osuna, C.E.; Lim, S.Y.; Deleage, C.; Griffin, B.D.; Stein, D.; Schroeder, L.T.; Omange, R.W.; Best, K.; Luo, M.; Hraber, P.T.; et al. Zika viral dynamics and shedding in rhesus and cynomolgus macaques. Nat. Med. 2016, 22, 1448–1455. [Google Scholar] [CrossRef] [PubMed]
  65. Foy, B.D.; Kobylinski, K.C.; Chilson Foy, J.L.; Blitvich, B.J.; Travassos da Rosa, A.; Haddow, A.D.; Lanciotti, R.S.; Tesh, R.B. Probable non-vector-borne transmission of Zika virus, Colorado, USA. Emerg. Infect. Dis. 2011, 17, 880–882. [Google Scholar] [CrossRef]
  66. Huits, R.; De Smet, B.; Arien, K.K.; Van Esbroeck, M.; Bottieau, E.; Cnops, L. Zika virus in semen: A prospective cohort study of symptomatic travellers returning to Belgium. Bull. World Health Organ. 2017, 95, 802–809. [Google Scholar] [CrossRef]
  67. Mead, P.S.; Duggal, N.K.; Hook, S.A.; Delorey, M.; Fischer, M.; Olzenak McGuire, D.; Becksted, H.; Max, R.J.; Anishchenko, M.; Schwartz, A.M.; et al. Zika Virus Shedding in Semen of Symptomatic Infected Men. N. Engl. J. Med. 2018, 378, 1377–1385. [Google Scholar] [CrossRef]
  68. Paz-Bailey, G.; Rosenberg, E.S.; Sharp, T.M. Persistence of Zika Virus in Body Fluids-Final Report. N. Engl. J. Med. 2019, 380, 198–199. [Google Scholar] [CrossRef]
  69. Kurscheidt, F.A.; Mesquita, C.S.S.; Damke, G.; Damke, E.; Carvalho, A.; Suehiro, T.T.; Teixeira, J.J.V.; da Silva, V.R.S.; Souza, R.P.; Consolaro, M.E.L. Persistence and clinical relevance of Zika virus in the male genital tract. Nat. Rev. Urol. 2019, 16, 211–230. [Google Scholar] [CrossRef]
  70. Uraki, R.; Hwang, J.; Jurado, K.A.; Householder, S.; Yockey, L.J.; Hastings, A.K.; Homer, R.J.; Iwasaki, A.; Fikrig, E. Zika virus causes testicular atrophy. Sci. Adv. 2017, 3, e1602899. [Google Scholar] [CrossRef] [Green Version]
  71. Ma, W.; Li, S.; Ma, S.; Jia, L.; Zhang, F.; Zhang, Y.; Zhang, J.; Wong, G.; Zhang, S.; Lu, X.; et al. Zika Virus Causes Testis Damage and Leads to Male Infertility in Mice. Cell 2016, 167, 1511–1524.e10. [Google Scholar] [CrossRef] [PubMed]
  72. Duggal, N.K.; Ritter, J.M.; Pestorius, S.E.; Zaki, S.R.; Davis, B.S.; Chang, G.J.; Bowen, R.A.; Brault, A.C. Frequent Zika Virus Sexual Transmission and Prolonged Viral RNA Shedding in an Immunodeficient Mouse Model. Cell Rep. 2017, 18, 1751–1760. [Google Scholar] [CrossRef] [PubMed]
  73. Koide, F.; Goebel, S.; Snyder, B.; Walters, K.B.; Gast, A.; Hagelin, K.; Kalkeri, R.; Rayner, J. Development of a Zika Virus Infection Model in Cynomolgus Macaques. Front. Microbiol. 2016, 7, 2028. [Google Scholar] [CrossRef] [PubMed]
  74. Polonio, C.M.; de Freitas, C.L.; Zanluqui, N.G.; Peron, J.P.S. Zika virus congenital syndrome: Experimental models and clinical aspects. J. Venom. Anim. Toxins Incl. Trop. Dis. 2017, 23, 41. [Google Scholar] [CrossRef] [PubMed]
  75. Bido-Medina, R.; Wirsich, J.; Rodriguez, M.; Oviedo, J.; Miches, I.; Bido, P.; Tusen, L.; Stoeter, P.; Sadaghiani, S. Impact of Zika Virus on adult human brain structure and functional organization. Ann. Clin. Transl. Neurol. 2018, 5, 752–762. [Google Scholar] [CrossRef]
  76. Creange, A. Guillain-Barre syndrome: 100 years on. Rev. Neurol. 2016, 172, 770–774. [Google Scholar] [CrossRef]
  77. Goodfellow, J.A.; Willison, H.J. Guillain-Barre syndrome: A century of progress. Nat. Rev. Neurol. 2016, 12, 723–731. [Google Scholar] [CrossRef]
  78. Willison, H.J.; Jacobs, B.C.; van Doorn, P.A. Guillain-Barre syndrome. Lancet 2016, 388, 717–727. [Google Scholar] [CrossRef]
  79. Smith, D.R.; Hollidge, B.; Daye, S.; Zeng, X.; Blancett, C.; Kuszpit, K.; Bocan, T.; Koehler, J.W.; Coyne, S.; Minogue, T.; et al. Neuropathogenesis of Zika Virus in a Highly Susceptible Immunocompetent Mouse Model after Antibody Blockade of Type I Interferon. PLoS Negl. Trop. Dis. 2017, 11, e0005296. [Google Scholar] [CrossRef]
  80. Dowall, S.D.; Graham, V.A.; Rayner, E.; Atkinson, B.; Hall, G.; Watson, R.J.; Bosworth, A.; Bonney, L.C.; Kitchen, S.; Hewson, R. A Susceptible Mouse Model for Zika Virus Infection. PLoS Negl. Trop. Dis. 2016, 10, e0004658. [Google Scholar] [CrossRef] [Green Version]
  81. Zmurko, J.; Marques, R.E.; Schols, D.; Verbeken, E.; Kaptein, S.J.; Neyts, J. The Viral Polymerase Inhibitor 7-Deaza-2’-C-Methyladenosine Is a Potent Inhibitor of In Vitro Zika Virus Replication and Delays Disease Progression in a Robust Mouse Infection Model. PLoS Negl. Trop. Dis. 2016, 10, e0004695. [Google Scholar] [CrossRef] [PubMed]
  82. Parke, D.W., 3rd; Almeida, D.R.; Albini, T.A.; Ventura, C.V.; Berrocal, A.M.; Mittra, R.A. Serologically Confirmed Zika-Related Unilateral Acute Maculopathy in an Adult. Ophthalmology 2016, 123, 2432–2433. [Google Scholar] [CrossRef] [PubMed]
  83. Furtado, J.M.; Esposito, D.L.; Klein, T.M.; Teixeira-Pinto, T.; da Fonseca, B.A. Uveitis Associated with Zika Virus Infection. N. Engl. J. Med. 2016, 375, 394–396. [Google Scholar] [CrossRef] [PubMed]
  84. Manangeeswaran, M.; Kielczewski, J.L.; Sen, H.N.; Xu, B.C.; Ireland, D.D.C.; McWilliams, I.L.; Chan, C.C.; Caspi, R.R.; Verthelyi, D. ZIKA virus infection causes persistent chorioretinal lesions. Emerg. Microbes Infect. 2018, 7, 96. [Google Scholar] [CrossRef]
  85. Singh, P.K.; Guest, J.M.; Kanwar, M.; Boss, J.; Gao, N.; Juzych, M.S.; Abrams, G.W.; Yu, F.S.; Kumar, A. Zika virus infects cells lining the blood-retinal barrier and causes chorioretinal atrophy in mouse eyes. JCI Insight 2017, 2, e92340. [Google Scholar] [CrossRef]
  86. Singh, P.K.; Kasetti, R.B.; Zode, G.S.; Goyal, A.; Juzych, M.S.; Kumar, A. Zika Virus Infects Trabecular Meshwork and Causes Trabeculitis and Glaucomatous Pathology in Mouse Eyes. mSphere 2019, 4, e00173-19. [Google Scholar] [CrossRef]
  87. London, A.; Benhar, I.; Schwartz, M. The retina as a window to the brain-from eye research to CNS disorders. Nat. Rev. Neurol. 2013, 9, 44–53. [Google Scholar] [CrossRef]
  88. Aid, M.; Abbink, P.; Larocca, R.A.; Boyd, M.; Nityanandam, R.; Nanayakkara, O.; Martinot, A.J.; Moseley, E.T.; Blass, E.; Borducchi, E.N.; et al. Zika Virus Persistence in the Central Nervous System and Lymph Nodes of Rhesus Monkeys. Cell 2017, 169, 610–620.e4. [Google Scholar] [CrossRef]
  89. Hirsch, A.J.; Smith, J.L.; Haese, N.N.; Broeckel, R.M.; Parkins, C.J.; Kreklywich, C.; DeFilippis, V.R.; Denton, M.; Smith, P.P.; Messer, W.B.; et al. Zika Virus infection of rhesus macaques leads to viral persistence in multiple tissues. PLoS Pathog. 2017, 13, e1006219. [Google Scholar] [CrossRef]
  90. Silveira, E.L.V.; Rogers, K.A.; Gumber, S.; Amancha, P.; Xiao, P.; Woollard, S.M.; Byrareddy, S.N.; Teixeira, M.M.; Villinger, F. Immune Cell Dynamics in Rhesus Macaques Infected with a Brazilian Strain of Zika Virus. J. Immunol. 2017, 199, 1003–1011. [Google Scholar] [CrossRef] [Green Version]
  91. O’Connor, M.A.; Tisoncik-Go, J.; Lewis, T.B.; Miller, C.J.; Bratt, D.; Moats, C.R.; Edlefsen, P.T.; Smedley, J.; Klatt, N.R.; Gale, M., Jr.; et al. Early cellular innate immune responses drive Zika viral persistence and tissue tropism in pigtail macaques. Nat. Commun. 2018, 9, 3371. [Google Scholar] [CrossRef] [PubMed]
  92. Gurung, S.; Nadeau, H.; Maxted, M.; Peregrine, J.; Reuter, D.; Norris, A.; Edwards, R.; Hyatt, K.; Singleton, K.; Papin, J.F.; et al. Maternal Zika Virus (ZIKV) Infection following Vaginal Inoculation with ZIKV-Infected Semen in Timed-Pregnant Olive Baboons. J. Virol. 2020, 94, e00058-20. [Google Scholar] [CrossRef] [PubMed]
  93. Watanabe, S.; Tan, N.W.W.; Chan, K.W.K.; Vasudevan, S.G. Assessing the utility of antivirals for preventing maternal-fetal transmission of zika virus in pregnant mice. Antivir. Res. 2019, 167, 104–109. [Google Scholar] [CrossRef]
  94. Andrade, C.B.V.; Monteiro, V.R.S.; Coelho, S.V.A.; Gomes, H.R.; Sousa, R.P.C.; Nascimento, V.M.O.; Bloise, F.F.; Matthews, S.G.; Bloise, E.; Arruda, L.B.; et al. ZIKV Disrupts Placental Ultrastructure and Drug Transporter Expression in Mice. Front. Immunol. 2021, 12, 680246. [Google Scholar] [CrossRef] [PubMed]
  95. Yau, C.; Low, J.Z.H.; Gan, E.S.; Kwek, S.S.; Cui, L.; Tan, H.C.; Mok, D.Z.L.; Chan, C.Y.Y.; Sessions, O.M.; Watanabe, S.; et al. Dysregulated metabolism underpins Zika-virus-infection-associated impairment in fetal development. Cell Rep. 2021, 37, 110118. [Google Scholar] [CrossRef]
  96. Huang, W.C.; Abraham, R.; Shim, B.S.; Choe, H.; Page, D.T. Zika virus infection during the period of maximal brain growth causes microcephaly and corticospinal neuron apoptosis in wild type mice. Sci. Rep. 2016, 6, 34793. [Google Scholar] [CrossRef] [Green Version]
Vaccines 10 01517 g001 550
Figure 1. Dissemination of ZIKV in multiple organs.
Figure 1. Dissemination of ZIKV in multiple organs.
Vaccines 10 01517 g001
Vaccines 10 01517 g002 550
Figure 2. Tissue-specific pathologies of ZIKV infection in animal models.
Figure 2. Tissue-specific pathologies of ZIKV infection in animal models.
Vaccines 10 01517 g002
Table
Table 1. ZIKV vaccine candidates in clinical phase 1 and 2.
Table 1. ZIKV vaccine candidates in clinical phase 1 and 2.
Vaccine PlatformNameImmunogenPhaseSponsor
DNAVRC5283prM/E2National Institute of Allergy and Infectious Diseases (NIAID)
GLS-5700prM/E1GeneOne Life Science/Inovio Pharmaceuticals
VRC-ZKADNA085-00-VPprM/E1NIAID
mRNAmRNA-1325prM/E1Moderna
Inactivated virionZPIVWhole virus1NIAID
PIZV or TAK-426Whole virus1Takeda
VLA1601Whole virus1Valneva Austria GmbH
PeptideMV-ZikaprM/E1Themis Bioscience
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Kim, S.; Shin, H.Y. Understanding the Tissue Specificity of ZIKV Infection in Various Animal Models for Vaccine Development. Vaccines 2022, 10, 1517. https://doi.org/10.3390/vaccines10091517

AMA Style

Kim S, Shin HY. Understanding the Tissue Specificity of ZIKV Infection in Various Animal Models for Vaccine Development. Vaccines. 2022; 10(9):1517. https://doi.org/10.3390/vaccines10091517

Chicago/Turabian Style

Kim, Suyeon, and Ha Youn Shin. 2022. "Understanding the Tissue Specificity of ZIKV Infection in Various Animal Models for Vaccine Development" Vaccines 10, no. 9: 1517. https://doi.org/10.3390/vaccines10091517

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop